The effect of the area under the plasma concentration vs time curve and the maximum plasma concentration of esomeprazole on intragastric pH

Objective: The aim of this study was to create a useful model of the effect of the area under the plasma concentration vs time curve (AUC) and the maximum plasma concentration (C-max) of esomeprazole on intragastric pH, measured as the percentage of total time with intragastric pH above 4 (%pH > 4) during a 24-h period. Methods: The evaluation is based on esomeprazole data from two crossover studies. In the first study (n = 36), intragastric pH and plasma concentrations were measured on day 5 of repeated once-daily 20-mg and 40-mg doses of esomeprazole during fasting conditions. In the second study (n = 24), measurements were made on days 1 and 5 of repeated once-daily dosing with 40 mg of esomeprazole under fasting and fed conditions. A model was applied in which the logistic function of %PH > 4 was assumed to be linearly dependent on log-transformed AUC and C-max. The effects of repeated dosing and of fed relative to fasting conditions were included in the model, and the interindividual variation in %PH > 4 was accounted for. Results: The effect of the pharmacokinetic variables AUC and C-max of esomeprazole on %PH > 4 can be adequately described by a model using a logistic function for %PH > 4 and a normally distributed error. In this model, log-transformed AUC and C-max were both statistically significant. The model showed that for a fixed AUC, a decrease in C-max gives an increase in %PH > 4. A decrease in AUC, keeping C-max fixed, gives a decrease in %PH > 4, but a simultaneous decrease in C-max and AUC will result in a less pronounced decrease in %PH > 4. The model may be used for predicting differences in %PH > 4 between two formulations, based on assessments of AUC and C-max. Repeated dosing gave an increased %PH > 4, where approximately half of the increase stemmed from increased AUC and C-max, and the rest could be attributable to the persistent blockade of the proton pumps. Food intake reduced AUC and C-max but had no obvious effect on %pH > 4, which is explained by a prolonged time period with quantifiable plasma concentrations. Conclusion: The effect of the pharmacokinetic variables AUC and C-max of esomeprazole on %PH > 4 can be adequately described by a model using a logistic function for %PH > 4 and a normally distributed error.